Nanopore chip with n-type semiconductor

ABSTRACT

An apparatus and method for making a nanopore chip exhibiting one of low photosensitivity, low electrical noise, and low electrical drift. The apparatus provides a thin insulating diaphragm containing a nanopore, the diaphragm being supported on a rigid semiconductor frame, the semiconductor frame having N-type doping in those regions which are to be capacitively coupled to an ionic solution. Also disclosed is a method of making the apparatus.

TECHNICAL FIELD

The invention relates generally to the field of nanopores and moreparticularly to an apparatus and method for making a nanopore chipexhibiting one of low photosensitivity, low electrical noise, and lowelectrical drift.

BACKGROUND

Manipulating matter at the nanometer scale is important for manyelectronic, chemical and biological advances (See Li et al., “Ion beamsculpting at nanometer length scales”, Nature, 412: 166-169, 2001). Suchtechniques as “ion beam sculpting” have shown promise in fabricatingmolecule scale holes and nanopores in thin insulating membranes. Thesepores have also been effective in localizing molecular-scale electricaljunctions and switches (See Li et al., “Ion beam sculpting at nanometerlength scales”, Nature, 412: 166169, 2001).

Artificial nanopores have been fabricated by a variety of researchgroups with a number of materials. Generally, the approach is tofabricate these nanopores in a solid-state material or a thinfreestanding diaphragm of material supported on a frame of thick siliconto form a nanopore chip. Some materials that have been used to date forthe diaphragm material include silicon nitride and silicon dioxide.These materials are insulators, with resistivity typically greater than10¹⁰ Ohm-cm. In contrast, silicon is a semiconductor with a resistivityless than 10⁴ Ohm-cm, and for practical purposes can be considered to bea near short circuit in relation to the insulating diaphragm material.

Data is typically obtained from an artificial nanopore by placing thenanopore in an aqueous ionic solution of potassium chloride (KCl),commonly referred to as a “buffer” solution, the solution containingmolecules of a polynucleotide such as double-stranded DNA. See, forexample, “DNA molecules and configurations in a solidstate nanoporemicroscope,” by Jiali Li, Marc Gershow, Derek Stein, Eric Brandin, andJ. A. Golovchenko, Nature Materials, Vol. 2, September 2003, pp 611-615,which is incorporated herein in its entirety by reference. FIG. 1 b fromthat reference is reproduced herein as FIG. 1. With reference to FIG. 1,during use a voltage V is applied across the nanopore by electrodeslocated in the “Cis” and “Trans” volumes, and the resulting current ismeasured as an “Ionic current signal.”

Communication between the inventor and the authors of the abovereference revealed that a problem with the use artificial nanoporesfabricated to date has been high photosensitivity, necessitating takingdata in the dark. Therefore an approach is needed which provides lowphotosensitivity. It is also desirable to minimize noise and drift inthe ionic current signal.

Other investigators have proposed building nanopores in semiconductingmembranes with surface insulators on the semiconductors. See, forexample, U.S. Pat. No. 6,413,792, “Ultra-fast Nucleic Acid SequencingDevice and a Method for Making and Using Same,” and associated worldfilings WO01/81908 and WO01/81896. However, because the semiconductor insuch a membrane provides a near short circuit in comparison to aninsulator, the characteristics of the resulting ionic current signal areseverely degraded if such a semiconducting membrane is used in theapparatus shown in FIG. 1

These and other problems with the prior art processes and designs areobviated by the present invention. The references cited in thisapplication infa and supra, are hereby incorporated in this applicationby reference. However, cited references or art are not admitted to beprior art to this application.

SUMMARY OF THE INVENTION

The invention provides an apparatus and method for nanoporeconstruction.

The apparatus comprises a nanopore chip comprising a nanopore disposedin an insulating diaphragm, the diaphragm being supported by a rigidframe, the rigid frame comprising an N-type semiconductor in thoseportions of the nanopore chip which are intended to be capacitivelycoupled to an ionic solution.

The invention also provides a method of making the apparatus. The methodof making the apparatus comprises fabricating a nanopore chip by

-   -   providing a semiconductor substrate,    -   providing N-type doping at those portions of the substrate which        are to be capacitively coupled to an ionic solution,    -   forming an insulating diaphragm supported by the substrate,    -   forming a nanopore disposed in the diaphragm.

The steps of the above method may be varied in any logically consistentfashion. For example, the nanopore may be formed before or after thediaphragm is formed. The providing of N-type doping may occur before orafter the diaphragm is formed.

BRIEF DESCRIPTION OF THE FIGURE

FIG. 1 reproduces FIG. 1 b from “DNA molecules and configurations in asolidstate nanopore microscope,” by Jiali Li, Marc Gershow, Derek Stein,Eric Brandin, and J. A. Golovchenko, Nature Materials, Vol. 2, September2003, pp 611-615

FIG. 2 is a cross section of a nanopore chip comprising the apparatus ofthe present invention.

DETAILED DESCRIPTION OF THE INVENTION

Before describing the present invention in detail, it is to beunderstood that this invention is not limited to specific compositions,method steps, or equipment, as such may vary. It is also to beunderstood that the terminology used herein is for the purpose ofdescribing particular embodiments only, and is not intended to belimiting. Methods recited herein may be carried out in any order of therecited events that is logically possible, as well as the recited orderof events.

Unless defined otherwise below, all technical and scientific terms usedherein have the same meaning as commonly understood by one of ordinarskill in the art to which this invention belongs. Still, certainelements are defined herein for the sake of clarity. In the event thatterms in this application are in conflict with the usage of ordinaryskill in the art, the usage herein shall be controlling.

Where a range of values is provided, it is understood that eachintervening value, to the tenth of the unit of the lower limit unlessthe context clearly dictates otherwise, between the upper and lowerlimit of that range, and any other stated or intervening value in thatstated range, is encompassed within the invention. The upper and lowerlimits of these smaller ranges may independently be included in thesmaller ranges, and are also encompassed within the invention, subjectto any specifically excluded limit in the stated range. Where the statedrange includes one or both of the limits; ranges excluding either orboth of those included limits are also included in the invention.

Methods recited herein may be carried out in any order of the recitedevents that is logically possible, as well as the recited order ofevents.

It must be noted that, as used in this specification and the appendedclaims, the singular forms “a”, “an,” “the,” and “one of” include pluralreferents unless the context clearly dictates otherwise.

The term “about” refers to being closely or approximate to, but notexactly. A small margin of error is present. This margin of error wouldnot exceed plus or minus the same integer value. For instance, about 0.1micrometers would mean no lower than 0 but no higher than 0.2.

The term “nanopore” refers to any pore or hole between at least a pairof electrodes or a hole in a solid substrate. Nanopores can range insize and can range from about 1 nm to about 300 nm. Most effectivenanopores have been roughly around 2 nm.

The term “adjacent” refers to anything that is near, next to oradjoining. For instance, a tensile layer may be near a compressivelayer, next to a compressive layer or adjoining a compressive layer.

FIG. 1 shows a cross section the apparatus of the present inventionpackaged for use with associated ionic solutions and electronics. Thefigure is not to scale, and some features are greatly exaggerated forpurposes of description. The nanopore is very small in comparison to thewidth of the diaphragm and is not explicitly shown in the drawing, butthat nanopore sits in the thin diaphragm atop the “Chip containingnanopore detector,” herein called a “nanopore chip.”

FIG. 2 shows a cross section of the apparatus of the present inventionwith some associated packaging elements.

A detailed description of the operation of the apparatus of theinvention is as follows, with reference to FIGS. 1 and 2. A voltage V,typically on the order of 120 millivolts, is applied between the “Cis”volume 24 and “Trans” volume 26 of aqueous ionic KCl solution. DNAmolecules, which have a negative charge and are labeled “DNA” to denotethat charge, sit in the CIS volume 24 and are drawn by the voltagedifference between the Cis and Trans volumes 24 and 26 to the nanopore12 in the thin insulating diaphragm 14 atop the nanopore chip 10,through that nanopore 12, and into the Trans volume 26. At the same timean ionic stream, not shown, comprising negatively charged hydratedchlorine ions flow from Cis to Trans, and an ionic stream, not shown,comprising positively charged hydrated potassium ions flows from Transto Cis. Packaging element 20 confines the ionic solution to the Cisvolume 24 while packaging element 22 confines the ionic solution to theTrans volume 26.

The total measured “ionic current signal” comprises not only chargeflows due to the DNA, the chlorine ions, and the potassium ions, butalso comprises undesired displacement currents having transientcharacteristics (called “AC characteristics”) with some magnitude andsome frequency spectrum, but having zero net long-term characteristics(called “DC characteristics”). These displacement currents occur acrossthe insulating diaphragm 14 in which the nanopore 12 sits, across thecapacitively-coupled interfaces 28 between the semiconductor frame 18and the Trans volume 26, and across the capacitively coupled interface30 between the semiconductor frame 18 and the Cis volume 24

At the same time, the current through the nanopore 12 has both a DCcharacteristic and an AC characteristic, the AC characteristic havingsome frequency spectrum.

If the desired ionic current through the nanopore overlaps in frequencywith the undesired displacement current, the desired signal is degradedto some extent.

To minimize the displacement current, one approach is to minimizecapacitance either through packaging design, through modification to thenanopore chip for example as in patent application (Docket 10021090-1,APPARATUS AND METHOD FOR MAKING A LOW CAPACITANCE ARTIFICIAL NANOPORE,which is incorporated herein in its entirety by reference), or both.

However, some capacitive coupling of ionic solution to the semiconductorframe 18 of nanopore chip 10 still occurs, especially in the region 28beneath the diaphragm where bare etched silicon adjacent the diaphragmedge touches the Trans volume 26, and also in regions of the Cis volume24 where liquid contact occurs to thin insulator regions on surfaces ofthe semiconductor chip.

Previous nanopore chips have been fabricated using p-type silicon by theauthors of the above-referenced “DNA molecules and configurations in asolidstate nanopore microscope,” by Jiali Li, Marc Gershow, Derek Stein,Eric Brandin, and J. A. Golovchenko, Nature Materials, Vol. 2, September2003, pp 611-615. It has been found that these chips exhibit highphotosensitivity of the measured ionic current signal, thus requiringdark ambient conditions during measurement in order to obtain usefuldata.

It is the present inventor's belief that such photosensitivity is theresult of capacitive displacement currents resulting from hole-electronpair generation in a depletion region near the bare surface of thep-type silicon, corresponding to region 28 of the present invention, andnear insulator surfaces corresponding to region 30 of the presentinvention. In addition it is the inventor's belief that thermalvariations and electrically induced variations in depletion region widthcause transient currents and signal drift with time constants on theorder of hours, thus degrading the measured signals.

The inventor has proposed the use of n-type silicon instead of p-typesilicon to fabricate the semiconductor frame 18 of nanopore chips in thebelief that such chips would have an accumulation region, rather than adepletion region, near region 28 and region 30, and that such chipswould exhibit greatly reduced photosensitivity of the ionic current.Such chips have been fabricated, and the expected reduction inphotosensitivity has been achieved. As of this writing, no measurementsof transients and long-term drift have been conducted. The presentinvention is expected to show utility in reducing transients, electricalnoise, and electrical drift.

Experimental verification of the utility of the present invention wasgained using a silicon frame 18 comprising n-type silicon doped withphosphorous and having a resistivity in the range of 1-50 Ohm-cm. Othern-type dopants known in the art, including but limited to arsenic, maybe used, and other resistivities may be used, including but not limitedto resistivities from 0.002 Ohm-cm to 10,000 Ohm-cm. Other n-typesemiconductors may be used, including but not limited to germanium andgallium arsenide, and for such other n-type semiconductors known n-typedopants may be used, including but not limited to phosphorous andarsenic.

It will be appreciated that, while the present invention is aimed towardutility in fabrication of nanopore structures, it may prove to haveutility for fabrication of other devices both known and unknown in whichan insulating diaphragm supported on a semiconductor frame is placedbetween two volumes of ionic conductor. Such devices include deviceswith microscale and nanoscale dimensions. Microscale dimensions aredefined to include dimensions from 100 nm to 1 mm, and nanoscaledimensions are defined to include dimension from 0.1 nm to 1 um.

Thus, the present invention comprises a chip apparatus for use in apackage comprising an ionic solution, the-chip apparatus having aninsulating diaphragm, one of a microscale and a nanoscale devicedisposed one of in or on the insulating diaphragm, and a semiconductorframe supporting the insulating diaphragm, wherein those portions of thesemiconductor frame which are to be capacitively coupled to an ionicsolution, the ionic solution also to be electrically coupled to the oneof a microscale and a nanoscale device, comprise an n-typesemiconductor, comprising typically n-type silicon.

Variations on the above apparatus will occur to those skilled in the artwithout departing from the scope and spirit of the present invention.

While FIG. 1 shows the cavity on the bottom side of the diaphragmextending entirely through the thickness of the semiconductor frame,this is not a necessity of the invention, and instead the cavity beneaththe diaphragm may occupy a limited portion of the thickness of thesemiconductor frame.

A limited area of p-type semiconductor may intrude into the portions ofthe semiconductor frame 18 which are to be capacitively coupled to anionic solution without significantly degrading the performance of thepresent invention. Such regions are expected to increasephotosensitivity, noise, and drift, but such increases will be toleratedas part of desirable performance tradeoffs when, for example, activeelectronic elements are integrated into the nanopore chip.

A limited area of semiconductor may intrude into the insulatingdiaphragm 14 without significantly degrading the performance of thepresent invention. Such regions are expected to increasephotosensitivity, noise, and drift, but such increases will be toleratedas part of desirable performance tradeoffs when, for example, activeelectronic elements are integrated into the nanopore chip.

A limited area of metal may intrude into the insulating diaphragm 14without significantly degrading the performance of the presentinvention. Such regions are expected to increase photosensitivity,noise, and drift, but such increases will be tolerated as part ofdesirable performance tradeoffs when, for example, active electronicelements are integrated into the nanopore chip.

The present invention also comprises a method of fabricating a chipapparatus for use in a package comprising an ionic solution, comprisingproviding a semiconductor frame, providing n-type semiconductor regionscomprising those portions of the semiconductor frame which are to becapacitively coupled to an ionic solution, providing an insulatingdiaphragm supported by the semiconductor frame, and providing one of amicroscale and a nanoscale device disposed one of in or on theinsulating diaphragm, the ionic solution also to be electrically coupledto the one of a microscale and a nanoscale device.

It will be appreciated that the fabrication sequence described above isby way of example only, and that there are others techniques well knownto those skilled in the art which may be used to arrive at the samefinal apparatus.

It will be appreciated that the fabrication of a nanopore may beaccomplished by means other than focused ion beam drilling and argon ionbeam sculpting described in Li et al., “Ion beam sculpting at nanometerlength scales”, Nature, 412: 166-169, 2001. For example, other knownmeans of fabricating a nanopore include masking with a nanoparticlefollowed by layer evaporation around the masking nanoparticle, nextfollowed by removal of the nanoparticle and etching within the holewhich had been masked by the nanoparticle. Such techniques, both knownand unknown, may be used to fabricate nanopores as part of the apparatusand method of the present invention.

1-11. (canceled)
 12. A nanopore apparatus comprising: a diaphragm; and asemiconductor frame for supporting said diaphragm, wherein saidsemiconductor frame comprises an n-type semiconductor.
 13. A nanoporeapparatus as recited in claim 12, wherein said apparatus comprises amicroscale device disposed in or on said diaphragm.
 14. A nanoporeapparatus as recited in claim 12, wherein said apparatus comprises ananoscale device disposed in or on said diaphragm.
 15. A nanoporeapparatus as recited in claim 12, wherein said apparatus comprises ananopore disposed in said diaphragm.
 16. A nanopore apparatus as recitedin claim 12, wherein said diaphragm is an insulating diaphragm.
 17. Ananopore apparatus as recited in claim 12, wherein said n-typesemiconductor is doped with a dopant having a resistivity ranging from0.002 Ohm-cm to 10,000 Ohm-cm.
 18. A nanopore apparatus as recited inclaim 17, wherein said n-type semiconductor is doped with a dopanthaving a resistivity ranging from 1 Ohm-cm to 50 Ohm-cm.
 19. A nanoporeapparatus as recited in claim 12, wherein said n-type semiconductorcomprises silicon.
 20. A nanopore apparatus as recited in claim 19,wherein said silicon comprising n-type semiconductor is doped with adopant chosen from a group comprising phospohorous and arsenic.
 21. Ananopore apparatus as recited in claim 12, wherein said n-typesemiconductor is chosen from a group comprising germanium and galliumarsenide.
 22. A nanopore apparatus as recited in claim 21, wherein saidn-type semiconductor is doped with a dopant chosen from a groupcomprising phospohorous and arsenic.
 23. A nanopore apparatus as recitedin claim 12, wherein said apparatus is a chip apparatus.
 24. A nanoporeapparatus comprising: (a) a diaphragm; (b) a semiconductor frame forsupporting said diaphragm, wherein said semiconductor frame comprises ann-type semiconductor; and (c) an aqueous fluid contacting saiddiaphragm.
 25. A nanopore apparatus as recited in claim 24, wherein saidapparatus comprises a microscale device disposed in or on saiddiaphragm.
 26. A nanopore apparatus as recited in claim 24, wherein saidapparatus comprises a nanoscale device disposed in or on said diaphragm.27. A nanopore apparatus as recited in claim 24, wherein said apparatuscomprises a nanopore disposed in said diaphragm.
 28. A nanoporeapparatus as recited in claim 24, wherein said diaphragm is aninsulating diaphragm.
 29. A nanopore apparatus as recited in claim 24,wherein said n-type semiconductor is doped with a dopant having aresistivity ranging from 0.002 Ohm-cm to 10,000 Ohm-cm.
 30. A nanoporeapparatus as recited in claim 29, wherein said n-type semiconductor isdoped with a dopant having a resistivity ranging from 1 Ohm-cm to 50Ohm-cm.
 31. A nanopore apparatus as recited in claim 24, wherein saidn-type semiconductor comprises silicon.
 32. A nanopore apparatus asrecited in 31, wherein said silicon comprising n-type semiconductor isdoped with a dopant chosen from a group comprising phospohorous andarsenic.
 33. A nanopore apparatus as recited in claim 24, wherein saidn-type semiconductor is chosen from a group comprising germanium andgallium arsenide.
 34. A nanopore apparatus as recited in claim 24,wherein said n-type semiconductor is doped with a dopant chosen from agroup comprising phospohorous and arsenic.
 35. A method for making ananopore apparatus comprising: providing a semiconductor framecomprising an n-type semiconductor, and positioning a diaphragm incontact with said semiconductor frame.
 36. A method as recited in claim35, wherein the n-type semiconductor comprises silicon.
 37. A method asrecited in claim 36, wherein the silicon is doped with a dopant chosenfrom a group comprising phospohorous and arsenic.
 38. A method asrecited in claim 35, wherein a microscale or nanoscale device is presentin or on said diaphragm.
 39. A method as recited in claim 38, whereinsaid microscale or nanoscale device comprises a nanopore.
 40. A methodcomprising: (a) providing an apparatus comprising: (i) a diaphragmhaving a nanopore disposed therein; (ii) a semiconductor frame forsupporting said diaphragm, wherein said semiconductor frame comprises ann-type semiconductor; and (iii) an aqueous solution in contact with saiddiphragm; (b) applying a voltage across said nanopore; and (c) measuringthe resultant current.